Evaluation of atorvastatin efficacy and toxicity on spermatozoa, accessory glands and gonadal hormones of healthy men: a pilot prospective clinical trial

Hanae Pons-Rejraji, Florence Brugnon, Benoit Sion, Salwan Maqdasy, Gerald Gouby, Bruno Pereira, Geoffroy Marceau, Anne-Sophie Gremeau, Joel Drevet, Genevieve Grizard, Laurent Janny, Igor Tauveron, Hanae Pons-Rejraji, Florence Brugnon, Benoit Sion, Salwan Maqdasy, Gerald Gouby, Bruno Pereira, Geoffroy Marceau, Anne-Sophie Gremeau, Joel Drevet, Genevieve Grizard, Laurent Janny, Igor Tauveron

Abstract

Background: Recommendations for cardiovascular disease prevention advocate lowering both cholesterol and low-density lipoprotein cholesterol systemic levels, notably by statin intake. However, statins are the subject of questions concerning their impact on male fertility. This study aimed to evaluate, by a prospective pilot assay, the efficacy and the toxicity of a decrease of cholesterol blood levels, induced by atorvastatin on semen quality and sexual hormone levels of healthy, normocholesterolaemic and normozoospermic men.

Methods: Atorvastatin (10 mg daily) was administrated orally during 5 months to 17 men with normal plasma lipid and standard semen parameters. Spermatozoa parameters, accessory gland markers, semen lipid levels and blood levels of gonadal hormones were assayed before statin intake, during the treatment, and 3 months after its withdrawal.

Results: Atorvastatin treatment significantly decreased circulating low-density lipoprotein cholesterol (LDL-C) and total cholesterol concentrations by 42% and 24% (p<0.0001) respectively, and reached the efficacy objective of the protocol. During atorvastatin therapy and/or 3 months after its withdrawal numerous semen parameters were significantly modified, such as total number of spermatozoa (-31%, p<0.05), vitality (-9.5%, p<0.05), total motility (+7.5%, p<0.05), morphology (head, neck and midpiece abnormalities, p<0.05), and the kinetics of acrosome reaction (p<0.05). Seminal concentrations of acid phosphatases (p<0.01), α-glucosidase (p<0.05) and L-carnitine (p<0.05) were also decreased during the therapy, indicating an alteration of prostatic and epididymal functions. Moreover, we measured at least one altered semen parameter in 35% of the subjects during atorvastatin treatment, and in 65% of the subjects after withdrawal, which led us to consider that atorvastatin is unsafe in the context of our study.

Conclusions: Our results show for the first time that atorvastatin significantly affects the sperm parameters and the seminal fluid composition of healthy men.

Trial registration: ClinicalTrials.gov NCT02094313.

NCT02094313

Figures

Figure 1
Figure 1
Atorvastatin effects on membrane cholesterol distribution, P-Tyr and acrosome reaction in spermatozoa. Membrane cholesterol distribution, P-Tyr and acrosome integrity were analysed in spermatozoa obtained from 17 normocholesterolaemic men before, during and 3 months after the end of treatment as described in Methods. P-Tyr patterns were assessed before (t = 0 h) and after (t = 3 h) incubating spermatozoa in capacitating conditionsd and visualized by western blotting using a monoclonal anti-phosphotyrosine antibody. To calibrate the signal for the amount of sperm protein, the same membranes were reprobed using a monoclonal anti-alpha-tubulin antibody. Acrosome integrity was assessed before (5 min) and after 3 h of incubation in capacitating conditions (3 h), by epifluorescence microscopy (x400) using PSA-FITC as a probe. A represents mean ± SEM of the percentage of sperm cells showing a redistribution of cholesterol with filipin labelling absent in the sperm head. Cholesterol distribution was estimated by epifluorescence microscopy (x400) using filipin as a probe. B represents typical patterns of protein tyrosine phosphorylation (P-Tyr) and α-tubulin in human spermatozoa. C represents P-Tyr signal normalized to the tubulin signal and the ratios were related to the basal signal obtained before incubation. Data are represented as mean ± SEM in arbitrary units (a.u.). D represents a fluorescence micrograph showing a sperm cell with an intact acrosome membrane (A pattern: marked fluorescence in the acrosome region) and a sperm cell without an acrosome membrane (AR pattern: no fluorescence or marked fluorescence along the equatorial segment). E represents mean ± SEM of the percentage of AR spermatozoa. *indicates values significantly different from those measured before atorvastatin intake with p < 0.05.
Figure 2
Figure 2
Effects of atorvastatin on human sperm vitality and progressive motility. Percentages of viable (A) and total motile (B) spermatozoa of the seventeen subjects are represented in the spider graphs before (control baseline values), during and 3 months after the end of treatment. *indicates patients having altered sperm parameters according to WHO standards.
Figure 3
Figure 3
Atorvastatin effects on markers of the accessory sex glands. The seminal levels of fructose (A) (seminal vesicle marker), acid phosphatases and citric acid (B (prostate markers), and alpha-glucosidase and L-carnitine (C and D) (epididymal markers) were measured in 17 normocholesterolaemic men before, during and 3 months after the end of treatment, as described in Methods. In A, B and C, bar represents mean ± SEM. **indicates values significantly different from those obtained before atorvastatin intake with p < 0.01 and ‡ indicates values significantly different from those measured during atorvastatin treatment with p < 0.05. In D, bars (white and coloured) and symbols (points and squares) represent mean ± SEM and percentages respectively of the subjects having normal (white) and altered (coloured) values of neutral α-glucosidase activity before, during and 3 months after the end of treatment.

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